Project 2: Molecular and clinical inputs affecting optimization of glioma therapy Project Summary / Abstract: Glioblastomas (GBM) are the most malignant and common of the primary brain tumors and are divided into several molecular subgroups denoted PN-GBM, MES-GBM and CL-GBM. Because of a subset of cells with stem-like properties, these tumors are relatively insensitive to DNA damaging agents, such as radiation (XRT), and are consequently highly resistant to therapy. In PN-GBM the stem-like cells live adjacent to blood vessels, in the perivascular niche (PVN). In other GBM subtypes, stem-like cells are distributed throughout the tumors. In order to identify better GBM therapies, we need to improve our understanding of the biology of stem- and non-stem-like GBM cells as a function of molecular subtype. We have previously demonstrated that the dynamic inter-conversion of these two cell types occurs within hours of therapy and can be successfully mathematically modeled, providing a basis for optimizing radiation schedules to maximize survival in mouse models of PN-GBM. However, optimum radiation administration schedules for other GBM subtypes are unknown. Additionally, standard of care calls for the administration of adjuvant temozolomide (TMZ) concurrently with radiation. Based on our preliminary data, we hypothesize that (1) a mathematical model of radiation and TMZ response in MES-GBM will be different than that for PN-GBM, (2) a mathematical model of radiation and TMZ response in MES-GBM will be different than that for PN-GBM, (3) there are biological characteristics of GBM that, if altered, would fundamentally enhance the responses of all GBMs regardless of subtype. We propose three specific aims to test these hypotheses: Aim 1: Improve our understanding of the PVN in PN-GBM and use this understanding to optimize combined TMZ/XRT therapy. Aim 2: Create a mathematical model of radiation response in MES-GBM where the stem cells are more evenly distributed. Aim 3. Identify strategies that would improve the standard of care for all GBM regardless of subtype. Our goal is to translate our findings into future clinical trials.